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Published online 14 June 2004 doi:10.1084/jem.20031675
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 12, 1701-1707
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SOCS1 Is a Suppressor of Liver Fibrosis and Hepatitis-induced Carcinogenesis

Takafumi Yoshida1,2, Hisanobu Ogata1, Masaki Kamio1, Akiko Joo1, Hiroshi Shiraishi1, Yoko Tokunaga2, Michio Sata2, Hisaki Nagai3, and Akihiko Yoshimura1

1 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
2 Second Department of Internal Medicine, Kurume University, Kurume 830-0011, Japan
3 Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kawasaki 211-0063, Japan

Address correspondence to Akihiko Yoshimura, Div. of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6823; Fax: 81-92-642-6825; email: yakihiko{at}bioreg.kyushu-u.ac.jp

Hepatocellular carcinomas (HCCs) mainly develop from liver cirrhosis and severe liver fibrosis that are established with long-lasting inflammation of the liver. Silencing of the suppressor of the cytokine signaling-1 (SOCS1) gene, a negative regulator of cytokine signaling, by DNA methylation has been implicated in development or progress of HCC. However, how SOCS1 contributes to HCC is unknown. We examined SOCS1 gene methylation in >200 patients with chronic liver disease and found that the severity of liver fibrosis is strongly correlated with SOCS1 gene methylation. In murine liver fibrosis models using dimethylnitrosamine, mice with haploinsufficiency of the SOCS1 gene (SOCS1–/+ mice) developed more severe liver fibrosis than did wild-type littermates (SOCS1+/+ mice). Moreover, carcinogen-induced HCC development was also enhanced by heterozygous deletion of the SOCS1 gene. These findings suggest that SOCS1 contributes to protection against hepatic injury and fibrosis, and may also protect against hepatocarcinogenesis.

Key Words: cytokine • STAT • TGF-ß • DNA methylation • hepatitis C virus

The online version of this article contains supplemental material.

Abbreviations used in this paper: ALT, alanine aminotransferase; DEN, diethylnitrosamine; DMN, dimethylnitrosamine; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; SMA, smooth muscle actin; SOCS1, suppressor of the cytokine signaling-1; STAT, signal transducer and activator of transcription.


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